Compositions for treating glaucoma

ABSTRACT

A glaucoma treating composition and method of treating glaucoma by administering the glaucoma treating composition to a patient are provided. The glaucoma treating composition comprises a carbostyril derivative, or acid addition salt thereof, having an intraocular pressure reducing activity in combination with an ophthalmically acceptable carrier, the barbostyril derivative being represented by the formula: ##STR1## wherein R 1  and R 2  are each lower alkyl, and the carbon-to-carbon bond between the 3-position and the 4-position of the carbostyril skeleton is a single bond or double bond.

TECHNICAL FIELD

This invention relates to compositions for treating glaucoma.

BACKGROUND ART

Glaucoma is attributable basically to a sustained or repeated increasein the intraocular pressure and causes functional and further organicdisorders to the eye. For the treatment of this disease, it isconsidered to be a matter of urgency to reduce the increased intraocularpressure to the normal level to maintain the proper visual function(Masakichi Mikuni and Kazuo Iwata, "Glaucoma," Kanehara Shuppan Co.,Ltd., 1968).

DISCLOSURE OF INVENTION

The glaucoma treating compositions of this invention comprise, as theactive component thereof, a carbostyril derivative represented by theformula ##STR2## wherein R¹ and R² are each lower alkyl, and thecarbon-to-carbon bond between the 3-position and the 4-position of thecarbostyril skeleton is a single bond or double bond, or an acidaddition salt thereof.

The lower alkyl groups represented by R¹ and R² in the formula (I) arestraight-chain or branched-chain alkyl groups having 1 to 4 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.Useful acid addition salts of the carbostyril derivatives represented bythe formula (I) are acid addition salts thereof which are usuallypharmaceutically acceptable and which include, for example, salts ofhydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, oxalicacid, maleic acid, fumaric acid, citric acid, tartaric acid, etc.

Given below are typical examples of the active compounds represented bythe formula (I) and useful for the glaucoma treating compositions ofthis invention.

8-Hydroxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril

8-Hydroxy-5-(1-hydroxy-2-tert-butylaminopropyl)carbostyril

8-Hydroxy-5-(1-hydroxy-2-ethylaminobutyl)-3,4-dihydrocarbostyril

8-Hydroxy-5-(1-hydroxy-2-isopropylaminobutyl)-3,4-dihydrocarbostyril

The compounds represented by the formula (I) and useful as the activecomponents are known compounds prepared, for example, by the processdisclosed in Published Examined Japanese Patent Application No.10994/1978. The active compounds have bronchodialatory activity anduseful for curing bronchial asthma.

This invention has been accomplished based on the finding that a groupof carbostyril derivatives known as agents for treating bronchial asthmainclude compounds which are capable of exhibiting an efficacy asglaucoma treating agents, namely, an intraocular pressure reducingeffect which is irrelevant to, and totally unexpected from, the efficacyas the bronchial asthma treating agent.

The glaucoma treating compositions of this invention can be formulatedas suitable dosage unit forms by admixing a derivative of the formula(I) or an acid addition salt thereof with a usual carrier for ophthalmicpreparations. The compositions can be in the form of any various usualdosage unit forms including ophthalmic ointments, ophthalmic solutions,etc. for local administration, and tablets, granules and injectionsolutions, etc. for general administration. It is especially preferableto use the compositions of this invention in the form of ophthalmicsolutions.

Although the dosage of the present treating compositions is notparticularly limited, the compositions are usually given at a daily doseof 0.01 to 0.5 mg, preferably 0.05 to 0.1 mg, for the adult, calculatedas the active component of the compositions. Preferably the compositionsare administered in two to three divided daily doses. It is usuallypreferable that the content of the active component contained in thecompositions range from about 0.04 to about 2% by weight.

The treating compositions of this invention can be prepared in the usualmanner with use of the derivative of the formula (I) or an acid additionsalt thereof as the active component, by admixing the active componentwith a suitable carrier or excipient and, if required, formulating themixture into the desired dosage unit form. The compositions, whenformulated in the form of ophthalmic ointments, ophthalmic solutions orinjection solutions, are further subjected to sterilization. Suitablecarriers or diluents are selected for use in accordance with the form ofthe compositions. Examples of carriers useful for the preparation ofophthalmic ointments are emulsifiable carriers, water-soluble carriersand suspendable carriers. Typical of such carriers are white vaseline,purified lanolin, liquid paraffin, etc. Typical of diluents forpreparing ophthalmic solutions is sterile distilled water.

Solubilizing agents, stabilizers, buffers, antioxidants, preservatives,etc. can further be incorporated into the compositions of thisinvention. Examples of useful solubilizing agents are sodiumcarboxymethyl cellulose; polyoxyethylene ethers such as polyoxyethylenelauryl ether and polyoxyethylene oleyl ether; higher fatty acid estersof polyethylene glycol such as polyethylene glycol monolaurate andpolyethylene glycol monooleate; fatty acid ester of polyoxyethylene suchas polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitanmonooleate; etc. Examples of useful stabilizers are hydroxypropylmethylcellulose, polyvinyl alcohol, carboxymethyl cellulose, hydroxyethylcellulose, glycerin, EDTA, etc. Examples of useful buffers are sodiumhydrogenphosphate, potassium hydrogenphosphate, boric acid, sodiumborate, citric acid, sodium citrate, tartaric acid, sodium tartrate,etc. Examples of useful antioxidants are sodium bisulfite, sodiumthiosulfite, ascorbic acid, etc. Examples of useful preservatives arechlorobutanol, benzalkonium chloride, cetylpyridinium chloride,phynylmercury salt, thimerosal, phenethyl alcohol, methylparaben,propylparaben, etc.

The compositions of this invention, when in the form of ophthalmicsolutions, should preferably be made isotonic with tears. For thispurpose, common salt or the like can be added to the compositions asdesired. It is desirable to adjust the pH of the ophthalmic solutions to5.5 to 8.5, preferably 6.5 to 7.5.

The glaucoma treating compositions of this invention thus prepared aregiven to patients by various methods in accordance with the form of thepreparations. Ophthalmic solutions are applied dropwise to the eye froma suitable container or sprayed onto the eye from an applicator.Ophthalmic ointments are also applied to the eye. Tablets and granulesare orally given, while injection solutions are administeredsubcutaneously, intramuscularly or intravenously. The desiredtherapeutic effect can be achieved in any of these cases.

The invention will be described below in greater detail with referenceto preparation examples and medicinal efficacy test, to which theinvention is not limited.

    ______________________________________                                        Preparation Example 1                                                         ______________________________________                                        8-Hydroxy-5-(1-hydroxy-2-isopropyl-                                           aminobutyl)carbostyril hydrochloride                                                                 0.2 g                                                  Benzalkonium chloride  0.01 g                                                 Sodium dihydrogenphosphate                                                                           0.56 g                                                 Potassium dihydrogenphosphate                                                                        0.8 g                                                  Distilled water        Suitable amount                                        Total                  100 ml                                                 ______________________________________                                    

The ingredients are dissolved in distilled water, and the solution issterilized by filtering with suitable filter paper to formulate aglaucoma treating composition of this invention in the form of anophthalmic solution.

    ______________________________________                                        Preparation Example 2                                                         ______________________________________                                        8-Hydroxy-5-(1-hydroxy-2-isopropyl-                                           aminobutyl-3,4-dihydrocarbostyril                                             hydrochloride          0.2 g                                                  Benzalkonium chloride  0.01 g                                                 Sodium dihydrogenphosphate                                                                           0.56 g                                                 Potassium dihydrogenphosphate                                                                        0.8 g                                                  Distilled water        Suitable amount                                        Total                  100 ml                                                 ______________________________________                                    

The ingredients are dissolved in distilled water, and the solution issterilized by filtering with suitable filter paper to formulate aglaucoma treating composition of this invention in the form of anophthalmic solution.

Efficacy test

A drop (about 25 μl) of the ophthalmic solution obtained in PreparationExample 1 is given twice a day, in the morning and evening, for threedays to each of the eyes of three male patients with open angleglaucoma. The intraocular pressure of the eye is measured between 10a.m. and 11 a.m. by Goldmann applanation tonometer. Table 1 shows theresults.

                  TABLE 1                                                         ______________________________________                                                 Intraocular pressure (mm Hg)                                                    Before                                                                        applica-   1 day    2 days 3 days                                  Patient    tion       later    later  later                                   ______________________________________                                        A     L.E.*    31.64      21.35  13.46  18.58                                       R.E.**   25.32      17.42  14.75  15.67                                 B     L.E.     38.85      23.78  24.52  21.27                                       R.E.     35.43      21.47  23.38  20.69                                 C     L.E.     23.57      18.68  14.75  16.37                                       R.E.     26.17      17.95  15.74  14.65                                 ______________________________________                                         *Left eye                                                                     **Right eye                                                              

Table 1 reveals that the glaucoma treating composition of this inventiongreatly reduces the intraocular pressure of the patients with glaucomaand produces an outstanding therapeutic effect.

The glaucoma treating composition obtained in Preparation Example 2according to this invention is tested for efficacy in the same manner asabove. The composition produces substantially the same effect ofreducing the intraocular pressure.

We claim:
 1. A method for treating glaucoma comprising administering toa patient a glaucoma treating composition comprising an intraoccularpressure reducing effective amount of a carbostyril derivative, or anacid addition salt thereof, in combination with a carrier suitable forophthalmic preparations, said carbostyril derivative being representedby the formula: ##STR3## wherein R¹ and R² are each lower alkyl, and thecarbon-to-carbon bond between the 3-position and the 4-position of thecarbostyril skeleton is a single or double bond.
 2. A method accordingto claim 1 wherein the composition is administered at a daily dose of0.01 to 0.5 mg calculated as the active component.
 3. A method accordingto claim 1 wherein the composition is administered at a daily dose of0.05 to 0.1 mg calculated as the active component.
 4. A method accordingto any one of claims 1-3, wherein the carbostyril derivative is a8-hydroxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril hydrochloride.5. A method according to claim 4 wherein the composition is in the formof an ophthalmic solution which is isotonic with tears and has a pH of5.5 to 8.5.
 6. A method according to claim 1 wherein the glaucomatreating composition comprises from about 0.04 to about 2% by weight ofthe carbostyril derivative.